Human papilloma virus (HPV) infection is the necessary cause of all cervical neoplasia and the majority of vulvar cancer. Large population-based studies show strong familial associations among anogenital cancers. However, the specific genetic factors that contribute to HPV anogenital carcinogenesis have not been comprehensively studied. Cell-mediated immune mechanisms, including HLA and type 1 and type 2 cytokines, are crucial determinants of the host response to HPV infection. In our Program Project Grant (CA 42792), we are currently funded to examine the association between HLA class I alleles and squamous cell cervical cancer risk. This application seeks funding to expand our investigation of the immunogenetics of HPV-related anogenital cancers. Specifically, using existing DNA specimens on 460 cervical adenocarcinomas, 426 squamous cell vulvar carcinomas, and 917 population controls, we will determine associations between HLA class I and class II alleles and risks of cervical adenocarcinoma and vulvar carcinoma. We will use microsatellite markers to determine extended haplotypes of HLA alleles associated with these cancers, and with squamous cell cervical cancer (n=453), to identify additional HLA-region loci potentially involved in HPV anogenital carcinogenesis. We also will determine associations between these anogenital cancers and multiple single nucleotide polymorphisms and haplotypes in 17 cytokine genes (primarily interleukins), and their receptors or receptor antagonists (40 genes in total), known or suspected of being involved in type 1 and 2 responses or anogenital carcinogenesis. Finally, we will test the hypothesis that squamous cell cervical cancer, cervical adenocarcinoma, and squamous vulvar carcinoma are associated with common genetic variation in the chemokine receptor gene CXCR4 (mutations in which are linked to inherited impaired immune response to HPV) and its ligand, SDF1. Secondary aims include exploration of gene-gene interactions (e.g., among ligand-receptor gene pairs and genes involved in common adaptive immune response pathways) and gene-environment interactions (cigarette smoking and cytokine or cytokine receptor genotypes). This study will be the most comprehensive assessment of anogenital cancer immunogenetics to date, and will provide new information on inherited predisposition to these cancers, with potential implications for the development and/or implementation of HPV vaccines.